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      The Importance of Brain Metastasis in EGFR Mutation Positive NSCLC Patients

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          Abstract

          Introduction. Brain metastasis is a poor prognostic marker in lung cancer. However it is not known whether amongst patients with EGFR mutation those with brain metastases have a worse outcome. Methods. We compared the survival outcomes between EGFR mutation positive patients with and without brain metastases. In this retrospective analysis of prospective database of all metastatic lung cancer patients at our centre between July 2009 and December 2012, patients were treated with either combination chemotherapy or oral TKI. All patients with brain metastases received whole brain radiation. Kaplan Meier method was used for survival analysis and compared using log rank test. Results. 101 patients with EGFR mutated, metastatic lung cancer were studied. Fourteen had brain metastases and 87 did not. The common EGFR mutations were exon 19 deletion (61.3%) and exon 21 L858R mutation (28.7%). Overall response was 64% in extracranial metastasis group as compared to 50% in brain metastasis group. There was a significant worsening of median OS in the patients with brain metastases (11.6 months) compared with only extracranial metastases (18.7 months), P = 0.029. Conclusion. Amongst patients with EGFR mutant NSCLC, the presence of brain metastases leads to a worse outcome as compared to patients with extracranial metastases alone.

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          Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.

          Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harboured EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed. Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.
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            Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis.

            A consecutive group of 259 patients with inoperable adenocarcinoma of the lung (ACL) were observed to define risk groups for and frequency of brain metastases together with prognosis. All patients received chemotherapy in a three-armed randomized trial. Brain metastases were diagnosed in 25 patients before protocol entry and in 37 during treatment. Brain autopsy was performed in 87 patients and was positive in 38 (44%). Eleven of these (29%) were not diagnosed clinically. Patients younger than 60 years had a somewhat higher overall frequency of brain metastases than older patients. Patients with initial performance status above 60% and patients responding to chemotherapy had higher risk for developing brain metastasis during treatment than other patients, probably because of the increasing cumulated risk for this complication with prolonged survival. Median survival after onset of brain metastases was 73 days and survival was significantly shorter for these patients than for patients without this complication at days 0, 90, 180, and 365 after protocol entry. Thus, brain metastases is a frequent complication in ACL and the frequency increases with prolonged survival. Survival after development of brain metastases is short and it is questionable whether the inclusion of this subgroup of ACL patients into experimental cytostatic treatments is justified.
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              EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer.

              A small subset of patients with nonsmall cell lung cancer (NSCLC) harbors mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The characteristics and behavior of brain metastases (BMs) in these patients have not been well described. The longitudinal records of all NSCLC patients who underwent EGFR mutation screening at our center from August 2004 to November 2008 were reviewed for eligibility, and 93 patients were identified who developed BM during the course of their disease. Survival was estimated using the Kaplan-Meier method and the log-rank test. Multivariable predictors were assessed via the Cox proportional hazards model. Among the 93 patients with BM, 41 (44%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations. Eighty-three percent of patients with BM were treated initially with whole brain radiation, either alone (53%) or in combination with craniotomy for neurosurgical resection (22%) or stereotactic radiosurgery (8%). Median survival from the time of BM was 11.7 months and was longer for patients with an EGFR mutation (14.5 vs 7.6 months, P = .09). On multivariable analysis, EGFR mutation (HR: 0.50, 95% CI: 0.30-0.82), age (HR: 1.03, 95% CI: 1.00-1.05), and active extracranial disease (HR: 3.30, 95% CI: 1.70-6.41) were independently associated with survival. In NSCLC patients with BM, EGFR mutation status is associated with improved survival, independent of age, functional status, extracranial disease status, and number of BMs.
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                Author and article information

                Journal
                Chemother Res Pract
                Chemother Res Pract
                CHERP
                Chemotherapy Research and Practice
                Hindawi Publishing Corporation
                2090-2107
                2090-2115
                2014
                7 December 2014
                : 2014
                : 856156
                Affiliations
                1Department of Medical Oncology, Tata Memorial Hospital, Dr. E. Borges Road, Parel, Mumbai, Maharashtra 400012, India
                2Department of Medical Oncology, Malabar Cancer Center, Moozhikkara, Kannur, Kerala 670103, India
                3Department of Radiodiagnosis, Tata Memorial Hospital, Dr. E. Borges Road, Parel, Mumbai, Maharashtra 400012, India
                4Department of Nuclear Medicine, Tata Memorial Hospital, Dr. E. Borges Road, Parel, Mumbai, Maharashtra 400012, India
                5Department of Pathology, Tata Memorial Hospital, Dr. E. Borges Road, Parel, Mumbai, Maharashtra 400012, India
                Author notes

                Academic Editor: Vassilis Georgoulias

                Article
                10.1155/2014/856156
                4274819
                25548673
                ad5197d7-5e09-4d22-bf64-801f63476122
                Copyright © 2014 Vanita Noronha et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 September 2014
                : 17 November 2014
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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